TW424087B - 1,3-dihydro-1-(phenylalkenyl)-2H-imidazol-2-one derivatives - Google Patents

Abstract

The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein R1 and R2 each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or substituted C1-10alkyl; R3 is hydrogen, halo or C1-6alkyloxy; R4 is hydrogen; cyano; optionally substituted C1-6alkyl; C1-6alkyloxycarbonyl or aryl; R5 is hydrogen; cyano; optionally substituted C1-6alkyl; C1-6alkyloxycarbonyl or aryl; Y is a direct bond or C1-3alkanediyl; -A-B- is a bivalent radical of formula -CR6=CR7- or -CHR6-CHR7-; L is hydrogen; optionally substituted C1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkylsulfonyl or arylsulfonyl; aryl is optionally substituted phenyl; Het is morpholinyl or optionally substituted piperidinyl, -piperazinyl, -pyridinyl;, -furanyl or -thienyl; having PDE IV and cytokine inhibiting activity. Further, pharmaceutical compositions, preparations and use as a medicine are described.

Description

__ ^ __ V. Description of the Invention (/) " ~ ~ The present invention relates to 1,3-monohydro-1- (phenylfluorenyl) _2Η-Mijun-2 with PDE IV and cytokinin inhibitory activity -Ketone derivatives and methods for their preparation, and further regarding their containing compositions and their use as medicaments. Ban Mingyi's Bismuth Punch Regulation: ::: Reveals Several 1- (phenylalkenyl) -2 · hydroxyimidazole Derivatives as Selective Inhibitors of 1 ¥ -type Phosphodimerase (PDE IV) . Unexpectedly, the specific 1,3-dihydro-1- (phenylalkenyl) -2H-imidazol-2-one derivative was severely inhibited. It was found that the compounds of the present invention can exhibit cytoplasm. Mitogen inhibitory activity. In view of these pharmaceutical properties, the compounds of the present invention have therapeutic uses in the treatment of disease states associated with abnormal fermentation or catalytic activity of PDE IV and / or disease states associated with excessive physiological damage to cytokinin, particularly It is an allergic, ectopic and inflammatory disease. The present invention relates to the 1,3-dihydro-1- (phenylalkenyl) -2H-oxazole-2-fluorene derivative of the following formula (please read the precautions on the back before filling this page)

Consumption cooperation by employees of the Central Bureau of Standards of the Ministry of Economic Affairs has printed its N-oxide form, pharmaceutically acceptable acid or basic addition salts, and its stereochemically isomeric forms, where: R1 and R2 are independent of each other It is hydrogen, C! -6 alkyl, difluoromethyl, trifluoromethyl, C3-6 ring surface group, saturated one or two hetero shoulders selected from oxygen, sulfur, or atmospheric 5-, 6- Or 7. Heterocyclyl, hydroindenyl, bicyclic This paper is in accordance with the Chinese National Standard (CNS) A4 (210x297), printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs "2 >, ύδ Α7 _________ V. Description of the invention ()) [2.2,1] -2-heptenyl, bicyclo [2.2,1] -2-heptyl, (: 1-6 alkyl phenyl group, aryl group peak group, or Two independently selected from the group consisting of aryl, pyridyl, quinyl, furanyl, C5_7 cycloalkyl substituted Ci-! G: fe groups and saturations containing one or two heteroatoms selected from oxygen, sulfur or nitrogen 5-, 6-or 7-membered heterocyclyl; R3 is hydrogen, halogen or alkoxy; R4 is hydrogen, cyano, Cm alkyl, alkoxycarbonyl, aryl or aryl, cyano, A few bases or C 1-6 Carbonyl substituted (^ _6 alkyl; R5 is hydrogen, cyano, CN6 alkyl, Ci.6 alkoxycarbonyl, aryl or Cl-6 substituted with aryl, cyano, carboxyl or Cl alkyloxy carboxyl Y is a direct bond or Ci_: T ^ diyl; -AB-is a divalent radical of the formula: -CR6 = CR7- (a-1); or -CHR6-CHR7- (a-2); where Each of R6 and R7 is independently hydrogen or CN4 alkyl; L is nitrogen, Cl-6, Cl-6, alkynyl, Cl_6, alkoxy, and one or two selected from Hydroxyl, Cw alkoxy, Cu4 alkoxycarbonyl, mono- and bis (CN4 alkyl) amino, aryl and Het, Cw alkenyl, aryl substituted C3-6 alkenyl, hexahydrocarbyl Hexahydropyridyl substituted with Ci_4 alkyl or aryl Cu4 alkyl, Cw alkylsulfonyl or arylcontinyl; aryl is phenyl or one, two or three selected from halogen, cyano , Cw alkyl, Ci-4 alkoxy, C5-6 cycloalkyl, trifluoromethyl, amine, nitro, carboxyl, Ch4 alkoxycarbonyl and Cm alkylcarbonylamino groups; this paper size applies China National Standards (CNS) A4 (210X297 mm) (Please read the notes on the back before filling P) * 11 4240ST at _____B7_ Five-described invention (now)

Het is morpholinyl, hexahydropyridyl 'substituted with ^ monoalkyl or aryl C! .4 alkyl substituted hexahydro &gt; Hexahydrocarbyl, Cyanolyl, Cyanyl, Pyridyl, Pyridyl, Furanyl, C ^ substituted by a C ??-4 alkyl or aryl Ci.4 group; Substituted furyl, thienyl, or thionyl substituted with (^ _4 alkyl or (^ _4 alkylcarbonylamino). Some compounds of formula (I) can also exist in their tautomeric forms, although this form although It is not clearly marked in the above formula, but it is included in the scope of the present invention. In R1 and R2, saturated 5-, 6-, or 7_ containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen Membered heterocyclic groups, suitably selected from heterocyclic groups, for example, tetrahydrofuranyl, dioxoalkyl, pyrrolidinyl, morpholinyl, hexahydropyridyl, hexahydropyridyl, and tetrahydropiperyl An aryl group, the heterocyclic group is connected to the C! "Alkyl group via any carbon atom or, if appropriate, via a nitrogen atom. Halogen used in the foregoing definition means fluorine, chlorine, bromine and iodine; d.4 fe group Means a straight chain containing 1 to 4 carbon atoms And branch-saturated nicotyl groups, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl and butyl printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs C! _6 alkyl refers to a group containing c? 4 alkyl fluorene and higher hard number similar groups containing 5 or 6 condensed atoms, for example, 2-methylbutyl, fluorenyl, and hexyl; Cw alkenyl Is defined as a straight or branched hydrocarbon group containing 3 to 6 carbon atoms and containing a double bond, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butylfluorenyl, etc., and the carbon atom to which the C3 · 6 allyl group is connected to a nitrogen atom is preferably saturated; C3_6 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl And cyclohexyl; Cl_3 gauge dibasic means straight or branched saturated divalent smoke containing 1 to 3 carbon atoms ~ 5 ~ This paper is in accordance with China National Standard (CNS) A4 specification (210X297 public director) Α7 Β7 A ^ 4〇δΊ V. Description of the invention (#) group, for example, fluorenyl, 1,2-ethylenediyl, ι_ethylenediyl, 1,3-propanediyl, 丨, 2- Propanediyl and ι, ι_propanediyl. References to pharmaceutically acceptable acid addition salts refer to acid addition salt forms which include compounds of formula (ί) which can be easily treated with a suitable acid in the base form. Suitable acids include, for example, inorganic Acids such as hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic acid, glycolic acid, bisacid, lactic acid, pyruvate, oxalic acid, malonate'succinic acid , Maleic acid, fumaric acid, malic acid 'tartaric acid, citric acid, methanesulfonic acid, hexylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, salicylic acid, Acids such as aminosalicylic acid and pamoic acid. Conversely, the acid addition salt form can also be converted to the free base form by treatment with a suitable base. The compounds of formula (I) containing acidic protons can also be converted into their non-toxic metal or amine addition salt forms after treatment with appropriate organic or inorganic bases. Suitable test salt forms include, for example, ammonium salts, Metal detection and soil test metal salts such as lithium, sodium, potassium, magnesium, calcium salts, etc., and organic base salts such as benzine, N-methyl-D-reducing glucosamine, hypamine salts, and With amino acids such as arginine, lysine and the like. The above-mentioned addition salts also include hydrates and solvent addition forms that can be formed by compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholates, and the like. The N-oxide form of a compound of formula (I) means that one or more of the nitrogen atoms of the compound of formula (I) is oxidized to a so-called oxide. As used herein, stereochemically isomeric forms, are defined as all possible isomeric forms that compounds of formula (1) may have, unless otherwise mentioned or referred to the Chinese Standard (CNS) Α4 Specifications (2ιοχ 297 public directors) (Please read the precautions on the back before filling out this page} 乂 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs _B7_ V. Description of the invention (f) It is stated that the chemical name of the compound represents all A mixture of possible stereochemical isomers, the mixture including all non-para-isomers and para-isomers of the basic molecular structure, more specifically, the stereocenter may have an R- or S-configuration, the formula ( I) Compounds can be produced as a mixture of E- and Z-types or pure E-types or pure Z-types. Some of the compounds of formula (I) and partial intermediates in the present invention may contain an asymmetric carbon atom, which can be used The known steps in this technique can obtain the pure compound and the intermediate, for example, non-palmomers can be separated by physical methods such as selective crystallization or chromatography techniques such as countercurrent split and liquid chromatography. Different palms Substances can be obtained from a racemic mixture. The racemic mixture is first converted to a mixture of non-paraisomeric salts or compounds with a suitable dissociating agent such as para palmitate, and then physical methods such as selective crystallization or chromatography are used. Techniques, such as liquid chromatography, separate the non-paraisomeric salt or compound mixture, and finally convert the separated non-paraisomeric salt or compound into the corresponding paraisomeric compound. As long as relevant The reaction is carried out in a specific stereo form. The pure stereochemically isomeric form of the compound of formula (I) can also be obtained from the appropriate intermediates and starting materials of the pure stereochemically isomeric form, pure and mixed stereochemically isomeric forms. The compounds of formula (I) in the form of structures are all included in the scope of the present invention. 3 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) A! In the following, the formula (Ϊ An alternative way to separate the isomeric forms of compounds and intermediates involves liquid chromatography, especially liquid chromatography using the opposite phase of palmarity, both in the following When used, the meaning of the compound of formula (I) also includes its N-oxide form, pharmaceutically acceptable acid or experimental addition salts and all stereochemically isomeric forms. National Standard (CNS) A4 Specification (210X_297mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (ό) — ~ The first group of specific compounds of formula (I) are applicable to them. Multiple columns specify: Ci_6 alkyl or C3,6 ring gauge and R2 is CN6 morpho; R3 is hydrogen; Y is a direct bond, methylene or 1,2-ethylenediyl; is a wind 'element , Ci_6 pit-based fluorenyl or diaryl fluorenyl is calcined, and L is hydrogen or diaryl CI_6 alkyl is preferred; -AB- is a divalent radical of formula (a- 丨), which is more preferably ( a_i) Anti 6 and Chi 7 are both divalent radicals of hydrogen. The second group of specific compounds of formula (I) are those in which one or more of the following applies: W is hydrogen, a saturated 5-, 6- or 7 containing one or two heteroatoms selected from oxygen, sulfur or nitrogen -Membered heterocyclyl, bicyclic [2.2.1] -2-heptenyl, 0: 1-6 alkylchityl, arylchityl, or independently selected from one to two via one or two , Thienyl, furyl, C3_7 cycloalkyl substituted Cbio alkyl, and saturated 5-, 6-, or 7-membered heterocyclyl containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen, R2 is Hydrogen, C3-6 ring alkyl, saturated 5-, 6- or 7-membered heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur or nitrogen, hydrogen indenyl, bicyclic [2 · 2.1] -2 -heptenyl, bicyclo [2.2.1] -2 -heptyl.fluorenyl>, C1.6 alkyl, fluorenyl, arylsulfonyl, or independently selected from aryl via one or two Radical, pyridinyl, thienyl, furyl, C3_7 cycloalkyl substituted Chift alkyl and saturated 5-, 6-, or 7-membered heterocycles containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen Ring group; R3 is halogen group or Cw alkoxy group; This paper size uses China National Standard (CNS) Standard 4 (210X297 mm) Ϊ́ 意 事 on the back ^ Please fill in this ear)-Order-A7 42… 87 V. Description of the invention (7) R4 is cyano, Cl_6 alkyl, aryl or via aryl, cyano, aryl, or Ci_6 alkane Cw alkyl substituted with oxycarbonyl; R5 is cyano, Cl- <5 alkyl, aryl, or alkyl substituted with aryl, cyano, carboxy, or ^^ alkoxycarbonyl; R is Alkyl, Cl.6, Ci-6, Ci-6, oxy, aryl, or Cu6 alkyl substituted with aryl, cyano, carboxy, or C &quot; alkoxycarbonyl, and R5 is not hydrogen; R3 is cyano , (^ _6 alkyl, c! _6 alkoxycarbonyl, aryl or Ch6 alkyl substituted with aryl, cyano, carboxyl or (^ _6 alkoxycarbonyl), and R4 is not hydrogen; -AB- is Divalent group of formula (a-2); B is 匚 alkylcarbonyl, (^ alkyl, Cw alkenyl, C3 6 alkenyl, Cw alkyl substituted with hydroxy or Ci_4 alkoxy group Sulfosulfanyl or aryl alkynyl. Useful subordinate groups included in this second group are compounds of their formula () where R4 is cyano, alkyl, aryl or via aryl, cyano, C6 alkyl substituted with carboxyl or C6 alkyloxycarbonyl; or R5 is cyano or Cl_6 Aryl, aryl, or Cr6 alkyl substituted with aryl, cyano, carboxy, or Cl-6 alkoxycarbonyl. Another useful accessory group included in this second group is their compounds of formula (1) where R1 is Hydrogen, saturated 5-, 6-, or 7-membered heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen, bicyclo [2.2.1] -2-heptenyl, Cb 6 gauge • Base group, arylsulfonyl group, or alkyl group substituted by one or two independently selected from the group consisting of molyl group, pennyl group, furyl group, C3_7 cycloalkyl group, and -9 ~ T paper scale applicable to China ( 2ι0χ297 public director (please read the precautions on the back before filling this page)

• 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 424087 A7 __ B7 V. Description of the Invention (孑) A saturated 5_, 6_ or 7_ member heterocyclic ring containing one or two heteroatoms selected from oxygen, sulfur or nitrogen base. The third group of specific compounds of the formula (I) are those in which one or more of the following provisions apply: R is wind, Ci-6 alkyl, monoisopropyl, difluoro 1 methyl, containing one or two selected from oxygen Saturated 5-, 6-, or 7-membered heterocyclyl, sulphur, or nitrogen heterocycle, hydrogen benzyl, bicyclo [2 · 2.: 1] -2-heptenyl, bicyclo [2.2.1]- 2-heptyl, Ci-6 alkynyl ~ gg, squaryl, or substituted by one or two independently selected from aryl, pyridyl, pyrimyl, furyl, and c3_7 cycloalkyl Ci-r «alkyl and a saturated 5-, 6-, or 7-membered heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen; R is hydrogen, (^ _6cycloalkyl, containing one or Two saturated 5-, 6- or 7-membered heterocyclic groups selected from the group consisting of oxygen, sulfur or nitrogen, hydrogen indenyl, bicyclo [2.2.1] -2-heptenyl, bicyclo [2.2.丨] -2-heptyl, (: 1-6 alkyl fluorenyl, aryl sulfonyl, or aryl, or at least one independently selected from aryl, p-methyl, sulfanyl, furan , C: U7 cycloalkyl substituted Cbu) alkyl and saturated 5-, 6-, or 7-membered heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen; R is a halogen group or Ci .6 Burning oxygen; R4 is aryl or Cw alkyl substituted by aryl, cyano, carboxyl or (^ _6 alkoxycarbonyl group +); printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Please fill in this page for more information) R3 is aryl or Ck alkyl substituted with aryl, cyano, carboxyl or alkoxycarbonyl; -AB- is the divalent radical of formula (a-2). This paper size applies to China National Standard (CNS) A4 Specification (2Ϊ0 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 424087 A7 _________B7 V. Description of the Invention (f) The useful subsidiary bases included in the third group are their equations (1 ) Compounds in which R4 is aryl or substituted with aryl, cyano, carboxyl, or c &quot; haloxy group; or R5 is aryl or cU6 substituted with aryl, cyano, carboxyl, or Cn6 alkoxycarbonyl Alkyl group. Another useful accessory group included in the third group is their compounds of formula () where R1 is hydrogen, C | 6 alkyl, difluoromethyl, trifluoromethyl, containing one or two A saturated 5_, 6_, or 7_ membered heterocyclic group selected from the group consisting of oxygen, sulfur, or nitrogen, hydrofluorenyl, bicyclo [2.2.1] -2-heptene Group, bicyclo [2.2.1] -2-heptanyl, Ck alkylsulfonyl, arylsulfonyl, or one or two independently selected from aryl, pyridyl, thienyl, furan Group, Ch cycloalkyl substituted Ckn alkyl group, and saturated 5-, 6-, or 7-membered heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen. The fourth group of specific formula (I ) Compounds are those in which one or more of the following applies: R1 is hydrogen, a saturated 5-, 6-, or 7-membered heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen, hydrogen indenyl , Bicyclo [2.2.1] -2-heptenyl, —% [2.2.1] -2-heptenyl, &lt; 31_6 '丨 redundant base 6 | [base, aryl base, or One or two independently selected from the group consisting of aryl, pyridyl, quinyl, furanyl, C3_7 cycloalkyl substituted CbH) alkyl and saturated with one or two heteroatoms selected from oxygen, sulfur or nitrogen5 -, 6- or 7-membered heterocyclic group; R2 is hydrogen, C3-6 cycloalkyl, saturated 5-, 6- or 7-membered heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur or nitrogen Cyclic, hydrogenated, bicyclo [2.2.1] -2-heptanyl, bicyclo [2.2.1] -2-heptanyl, (31.6 alkyl group, aryl group, Ci-ig alkynyl substituted with one or two independently selected from aryl, p-pyridyl, 11 ceryl, claranyl, C3-7 cycloalkynyl, and paper containing ~ 1 paper. Zhang scale is applicable to China National Ladder Standard (CNS) A4 Specification Ø 210X297 mm) (Please read the notes on the back before filling this page) Order A7 Β7 424087 ----——__ 5. Description of the invention (π ~ or two selected from oxygen, Saturated 5-, 6-, or 7-membered heterocyclic group of hetero atom of sulfur or nitrogen; R3 is a halogen group or C 1-6 alkyloxy group; R4 is hydrogen, cyano, Cw alkyl, cN6 alkoxycarbonyl or C ^ 6 alkyl substituted with cyano, carboxyl or C! _6 alkoxycarbonyl; R3 is hydrogen, cyano, Cm alkyl, cN6 alkoxycarbonyl or cyano, carboxyl or C ^ 6 alkoxy Carbonyl-substituted Cm alkyl; -AB- is a divalent group of formula (a-2). Useful accessory groups included in this fourth group are compounds of formula (丨) where R4 is hydrogen, cyano, Cw alkyl, C! -6 alkoxycarbonyl, or via cyano, carboxyl, or oxetan An oxycarbonyl-substituted c16 alkyl group; or R5 is hydrogen, cyano, alkyl, Ci-6 alkoxycarbonyl, or cU6 alkyl substituted with cyano, carboxy, or Ci 6 alkoxycarbonyl. Another useful accessory group included in this fourth group is their compounds of formula G) in which R1 is hydrogen, and contains one or two heteroatoms selected from oxygen, sulfur, or nitrogen. -Or 7-membered heterocyclyl, hydroindenyl, bicyclo [22 1] -2-heptenyl, bicyclo [2.2.1] -2-heptyl, Ck0 alkylsulfonyl, arylsulfonyl Fluorenyl, or Ct "substituted with one or two independently selected from aryl groups, fluorenyl, and fluorene. Fluorenyl and saturated 5-, 6-, or heteroatoms containing two =, oxygen, sulfur, or nitrogen 7-membered heterocyclyl. Preferred compounds are those of formula (ί) wherein R4 is ^ .6 alkyl substituted with cyanocarboxy or Cm alkoxycarbonyl; or is substituted with cyano, carboxy, or Cu Alkoxycarbonyl-substituted c [6 alkyl. —, And also preferred compounds are their compounds of formula (1) in which R1 contains one or two heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen; ; Or 7, _ member 12- (Please read the precautions on the back before filling out this page) -s Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Mtt Zhang scale 剌 t ® ϋ Jiaxian (CNS) {210 ^ 297 ^ ¾- 424087 at B7 V. Description of the invention (//) Heterocyclyl, bicyclic [2.2.1] -2-heptenyl, C] -6 alkylsulfonyl, arylsulfonyl, or Cl-II substituted with one or two independently selected from pyridyl, fluorenyl, furyl, Cg-7 cycloalkynyl, and containing one Or two saturated 5-, 6-, or 7-membered heterocyclic groups selected from heteroatoms of oxygen, sulfur, or gas. The best compound is: 1- [2- [3- (cyclopentyloxy) -4-methoxybenzyl-2-phenylethynyl] -1,3-dihydro-2H-imidazole- 2-keto; 3- (cyclofluorenyloxy)-/ S-[(2,3-dihydro-2-keto-1H-imidazol-1-yl) methylene] -4-methoxyphenyl Ethyl propionate; 1- [2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-propanyl] -3- (diphenylfluorenyl) -2H-imidazole- 2-ketone; its N-oxide form, pharmaceutically acceptable acid or basic addition salts, and its stereochemically isomeric form. Whenever used hereinafter, 1 ^ to &amp; 7, Y, -A-B-, and L refer to the definition of formula (I), unless otherwise specified. Compounds of formula (I) can generally be prepared by dehydrating the intermediate of formula (II) using dehydration techniques known in the art.

&gt;, 0 ^ ^ I dehydration reaction c ~ c- Y—n ^ nl-- mti 1 t, 'OH Η AB (please read the precautions on the back before filling this page) &quot; Order from the Central Ministry of Economic Affairs For example, the printing of local consumer cooperatives can be performed in an inert reaction solvent and the presence of an acid such as hydrogen acid or p-toluenesulfonic acid. The dehydration reaction can also be performed in an inert reaction solvent such as dichloromethane. For example, methanesulfonyl chloride or its functions, including the size of this paper, is applicable to China Standards (CNS) A4 (210X 297 mm) 424087 A7 B7 / Λ 5. Description of the invention (biological, and existence tests such as diethyl ethyl Under amine, the reaction rate can be promoted by removing and increasing the temperature. In this and the following preparations, the reaction products can be separated from the reaction medium 'and, if necessary, can be further purified according to methods well known in the art, for example, for example Extraction method, distillation method, crystallization method, milling method and chromatography method. To prepare a compound of formula (I) in which L is not hydrogen, the second is represented by dagger and the compound is represented by formula (Ia). 111) Intermediate and formula of W i 11 ig The four agents are reacted in an inert reaction solvent and in the presence of a suitable test such as butyl surface or sodium hydride, where X is a suitable counter ion such as autogen, and the scale salt type intermediate of formula (IV-a) is more reactive. Formula (IV_Ester Type Intermediate · Substitution. (Please read the precautions on the back before filling this page)

Then R5 X (. # 5) 3? + — CH-Y—N N — LT *. R A —B αν-a) 0 people

R5 C = C ~ γ.

N 0 people N—L;

A—B Order Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (Ia) Preparation of a compound of formula (I) in which L is argon. Among the intermediates, G is a suitable protective group, and then the removal and protection of the resulting intermediates is performed using the removal and protection techniques known in the art. ^ 'This paper size applies the Chinese National Standard (CNS) A4 specification (210X297) Firefly). 424087 A7 B7 V. Description of the invention (/ today R3 R20

R 丨 0 0 II C-R4 R5 Removal of protection reaction ⑽ X- (C6HS) 3P + ~ CH-Y—'N_G «I I A-Bcrv-b) o R3

In the formula, Y is limited to a compound of formula (Ia) in which C is a diyl group, the Y is represented by Y ′ and the compound is represented by the formula (Ia— 丨). The formula (v) Wittig reagent and the formula (V ia) The intermediate is reacted in an inert reaction solvent and in the presence of a suitable base such as butyl or sodium hydride. The scale salt type intermediate can be replaced with a more reactive phosphate (IV_a) phosphate intermediate. R3 R: 〇

RJ〇 (V) 0 〇 丨 1 person.

CH ~ P + (C6H5) 3X '+ r5_c_ γ, _ν, N_L,, t A-B (Please read the precautions on the back before filling this page)-Order (Vl-a) R3 R20

R * 0 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs R4 R5

i I C—C- Y'—Ν ', N—L ’

, I

AB 0-al) to prepare a compound of formula (I) in which Y is Y ', the compound is represented by the formula and can be obtained from the use of an intermediate of formula (IV-b) in the above reaction where G is a suitable protecting group, followed by Removal protection techniques known in the art remove and protect the intermediates thus obtained. -15- This paper size is applicable to Chinese National Standard (CNS) A # specifications (21〇297mm)

V. Description of the invention (cold r2o-

r'o (V) 〇? CH-P + (C6H5) 3X- + r5_J_ γ._Ν n-G fly f A-B (Vl-b) R20 R4 Removal protection reaction 〇

r! o meaning C ~~~~ C- Y1—N N—

A-B

abD to prepare a compound of formula (I) in which Y is Y ', the compound is represented by formula (jq) and can be obtained by subjecting 1,3-dihydro · 2Η-imidazol-2-one to an intermediate of formula (VII) -Alkylation, where is a reactive release group, for example halogen.

0 people si N \) A-B

R3 〇 'R4 R5 V C = C- Y'-n ^ N-L R: 0

Rl0

A-B (Please read the notes on the back before filling in this page j, 4. Order (vm) a-ο

L The Central Consumer Bureau of the Ministry of Economic Affairs printed the N-carbonization reaction at the Consumer Cooperative, which can be conveniently used in the presence of hydrogenation and hydrogenation> amine-based surface and inert tile. It can be lost in the ice bath as needed and in an ice bath. cool down. This reaction is preferably carried out under an inert reaction gas pressure, such as oxygen-free nitrogen, and a crown ether such as 1,4,7,10,13,16-hexaoxacyclooctadecane or the like is preferably added to the reaction mixture. The paper size of the physical test is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 4J4087 A7 B7

V. Description of the invention (AT = such as reference 2 · (2 · methoxyethoxy)] ethylamine, etc., an alternative method for preparing compounds of formula (1-1) by stirring is to accelerate the reaction. Intermediates where M is a suitable gold ion or metal complex ion, such as Li, (MgBr), B (0Η) 2+ or sn (CH3) 3+, and the 1,3-dihydroxy group of the appropriate formula (X) -2H-imidazol-2-one derivative reaction, in which W2 is a reactive release group, such as a fungus. R3 r2o R4 Rs

Μ + W2-C = C —Y.-N into N ~ L

A-B (M) (Please read the precautions on the back #Filling Tips f) k. (X) OX) The reaction can be carried out according to the summary of J. Med. Chem ,, 37 (11), 1550 (1994). Preparation of a compound of formula (I) in which -AB- is a group of formula (c-1), the compound is represented by formula (Ib-1-l) and can be easily obtained from the intermediate of formula (XI) or its function Sex derivatives are cyclized in the presence of a suitable acid such as hydrochloric acid

R3 RlO

r2o R4 R5 〇 0-Ci.4 alkyl group C = C —Y_-NH—C_NH—CH- &lt; p—O-Cm. Tiger-based (XI) R6

(1-bM) '17 ~ • 1 · 11 (CNsTMiFi 210X297 ^ ®). 4 24087, A7 B7 V. Description of the invention (M) The cyclization reaction can be carried out in an inert reaction solvent such as water, methanol or a mixture thereof. , Stirring and heating can promote the reaction rate. The compound of formula (Ib-1-l) can also be prepared by cyclizing an intermediate of formula (XII) or a functional derivative thereof in the presence of a suitable isocyanate such as potassium isocyanate or potassium trimethylsilyl isocyanate. .

R4 R5 R-0 (Please read the notes on the back before filling this page)? -CM. Pit-based isocyanate C = C ——0-CM alkyl R7 R6 (XII) Replacement of the compound of formula (Ibll) The preparation method is to react the intermediate of formula (XII) with a suitable cyanide such as potassium cyanide, so as to obtain a corresponding N-cyanide derivative, which can be further hydrolyzed in the presence of an acid such as hydrochloric acid to make the reaction mixture The pH is basic, and the corresponding urea derivative thus formed is further cyclized to a compound of formula (Ib-1-l) in the presence of an excess acid such as hydrochloric acid. 1) Cyanide 4, 2) Acid (pH &lt; 7) 〒R? -CM pit base 3) Excess acid C = c-Y-NH-CH-C-0-Cm ^ I:-Central Standard of the Ministry of Economic Affairs Printed by Bureau Consumers Cooperative

R-0 R7 R6 (ΧΙΟ -18- This paper size applies to the Chinese National Standard (CNS) A4 specification (21Ό × 297 mm) R3 r'o

r2o

r2o A ^ 4 Ο δ Τ A7 _____-__B7_ V. Description of the Invention (/ 7) A compound of formula (I-bl) in which -A-B- is a group of formula (a-2) is prepared. Ib-1-2) represents that it can be obtained from the ring of an intermediate of formula (XIII) or a functional derivative thereof in the presence of an inert reaction solvent and a suitable reagent such as phosgene, urea or N, N'-carbonyldiimidazole.化 反应。 Reaction. R4 R5 R6 R7

&gt; I 1 I — Y '^ NTi-CH-CH-NΉ ^ R6 R7 G * b-1 -2) The compounds of formula (i) can also be converted to each other using functional group conversion steps known in the art. For example, the compound of formula (Ia) can be prepared by reacting the compound of formula (I_b) with L'-W3 (XIV), where W3 is a reactive release group such as halogen atom 0 '(Please read the precautions on the back before (Fill in this page)-Ding, -1 ·

Rz〇

r! o R4 R5 JY, -N people NH l I AB Gb) W3-1— (Ia) λ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ~ 19 ~ (xiv) This paper standard is applicable to the national standards of the applying country (CNS) A4 specification (210X 297 public holidays) 424087 A7 B7 V. Description of the invention (β According to the known procedure of converting parametric nitrogen into its N-oxide form in this technology, the compound of formula (I) can also be used Into the corresponding N-oxide form, and the N-oxidation reaction is usually carried out by combining the starting material of formula (1) with 3-phenyl-2- (benzenesulfonyl) oxazine or with a suitable organic or Inorganic peroxide reactions. Suitable inorganic peroxides include, for example, hydrogen peroxide, metal or alkaline earth metal peroxides, such as sodium peroxide, potassium peroxide. Suitable organic peroxides include, for example, peroxy acids such as benzene peroxide. Carboxylic acids or phenylperoxycarboxylic acids substituted with haloxins such as 3-chlorobenzeneperoxycarboxylic acids, peroxyalkanoic acids such as peroxyacetic acid, alkylhydroxyperoxides such as tert-butylhydroxyperoxide. Suitable Solvents are, for example, water, lower alcohols such as ethanol, tobaccos such as methylbenzyl, coppers such as 2-butanone Functional hydrocarbons such as digas methane, and mixtures of such solvents. Intermediates of formula (II) can be prepared according to techniques known in the art, for example, in an inert reaction solvent such as tetrahydrofuran, the intermediate of formula (XV) Reacting with R4-M (XVI) where M is a metal ion or a metal complex such as Li + or (MgBr) + can prepare the formula (π) · intermediate. Oxygen and nitrogen. (Please read the notes on the back first, and then fill in the book 1) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

0D -20 This paper is a standard Chinese National Standard Vehicle (CNS) A4 (210X297). R-0

(XVII) (XV) 424087 A7 B7 V. Description of the invention (β) According to a method similar to the preparation of the compound of formula (1.1) from the intermediates (VII) and (VIII), the intermediate of formula (XVII) and the formula ( The intermediate of formula (XV) can be prepared by reacting the 1,3-dihydro-2Η · imidazol-2-one derivative of VIII). 0

X

H-N ^ N-L

'I

AB (VIH) The intermediate of formula (XVIII) is cyclized according to a method similar to the above to prepare the compound of formula (Ib-1-l) from the intermediate (XI) to prepare a formula in which the group of formula (a-1) is (XV) The intermediate is represented by the formula (XV-1). (Please read the notes on the back before filling this page),? Τ R] 〇

9 pounds? &lt; p-cM tiger-based C —Y-NH—C-NH-fH-f-alkyl R7 R6 (χνπΐ) (XV-S)

L Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs according to a method similar to the above-mentioned preparation of the compound of formula (Ibl, l) from the intermediate (XIII). 1) Intermediate. The paper size is suitable for wealth management (CNS) Α4 size (2⑴χ297々4) 424087

Five, description of the invention ()

? Hydroxyisocyanate c-c —Y-NH-fH-fO-CM alkyl-order-1) R7 R6 (XIX) According to the method similar to the above to prepare the compound of formula (Ib-1-2) 沬The intermediate of formula (XX) is cyclized to prepare an intermediate of formula (XV) in which-AB- is a group of formula (a-2), and the intermediate is represented by formula (χν-2).

0 R5 R6 R7 C—C —Y-NH—CH-CH-NH2 (XX) (Please read the precautions on the back before filling out this page) (XV-2) Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs print specific locations That is, the intermediate of formula (XVIII) can be prepared by first carrying out N-fluorination reaction of amine of formula (XXI) with phenyl chloroformate or a functional derivative thereof. The N-fluorination reaction can be easily performed in an inert reaction solvent. For example, in dichloromethane, benzene or methylbenzyl, if necessary, cooling in an ice bath, and in the presence of a base such as N, N-diethylethylamine or sodium bicarbonate, the intermediate thus obtained can be subsequently reacted with 2, 2- (diCi-4alkoxy) ethylamine or a functional derivative thereof reacts to form an intermediate of formula (VI), and the reaction can be easily performed in an inert reaction solvent such as 1,4-epoxy For example, in the presence of ν, N-diethylethylamine, and if necessary, in the presence of a catalyst example: ^ N, N-dimethyl than chloramine, mixing and increasing the temperature can promote the reaction rate. This paper size applies the Chinese National Standard (CNS) from the specifications (210χ 297 mm> 424037 A7 B7 V. Description of the invention (Λ /) R3 R'〇

R-〇0 R5 C-CH-Y-NH, (XXI) O-Cl-C-0— / ~ \ NH2-CH-C — O-Cm alkyl group = j R7 R &amp; (XVID) and 'make Intermediate of formula (XXI) with a suitable reagent such as 2,2- (diG-4alkoxy) ethyl isocyanate, [2,2 _ :( C1_6alkoxy) ethyl] carbamic acid benzene or Any functional derivative of the reagent can react directly to form an intermediate of formula (XVIII). (Please read the notes on the back before filling out this page) ‘今 R3 r'o

r2o or5 ii IC — CH-Y —NH2 (ΧΧΓ) 0-based 〇 = C = N-CH-C— 〇-Cm alkyl R7 R6 (XVni) or &lt; p-CMalkyl 〇_C_NH-CH-C- 〇-CMa! Kyl R7 R6 0 An intermediate of formula (XIX) can be prepared by reacting an amine of formula (XXI) with an intermediate of formula (xX11) where w4 is a reactive release group such as nansin. Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs R3 r'o

R: 0 OR5 Μ IC—CH-γ—N (XXI) Tiger-based W ^ -CH—t — Ό-CM alkyl · (XIX) R1 -23— R6 pCXII) The paper's dimensions are applicable to the Chinese National Standard (CNS) A4 specification (2 丨 〇 &lt; 2 mm) 42408T V. Description of the invention (public) The intermediate of formula (XXI) can be prepared according to the steps known in the art, and the intermediate of partial formula (XΧί) And its preparation methods are disclosed in wo 92 / '00968, WO 93/15044 and WO 93/15045. Moreover, an intermediate of formula (η) in which R3 is hydrogen, fluorene is a direct bond, and L is hydrogen is represented by formula (II-a), and can be prepared according to the reaction method shown in Figure 1. Legend 1

iii) (Please read the notes on the back before filling this page)

N ^ \? P-Cw Pit foundation N-C-NH-CH-C-R6 '' Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

R7 Ο-Cm ’pit base (XXVI) R3 〇 '? H meaning w) C—CH ^ -N ^ NH-~~, R4 H

r! o r2o

r O-Cw alkyl

The I-CH-C-R6 k i-Cw alkyl (XXV) flavor step 1 of Figure 1 relates to the gasification of an intermediate of formula (III) with a trimethylsilyl group in the presence of a suitable catalyst such as zinc iodide It reacts in an inert reaction solvent such as methane at one gas, so the intermediate (xym) is formed, where P is ~ 24 ~ This paper size applies to the National Solid Standard (CNS) A4 specification U0X297 mm. Printing A7 —---- B7 — 15. Description of the Invention (Clever) The trimethylsilyl protecting group or its functional derivative depends on the different nature of R1 to R4, and P can also be a lice. Then in step ii)., The nitrile derivative of formula (XXIII) can be reduced to the corresponding amine of formula (XXIV) according to techniques known in the art, for example in the presence of a suitable catalyst such as a Raney lens Using oxygen at 4 ° and then in step iii), the intermediate of formula (XXv) can be prepared from the intermediate of formula (XXIV) according to the above step of preparing the intermediate of formula (XViii). An alternative method of this step is to make formula ( XXIV) The intermediate is reacted with an imidazole derivative of the formula (XX VI) in a reactive solvent such as tetrahydrofuran, and it is preferably carried out between the standing temperature and the returning temperature. Finally, step iv) is about cyclizing an intermediate of formula (XXV) to an intermediate of formula (Ii-a) according to a method similar to the above-mentioned method of preparing an intermediate of formula (χν · 丨) from the intermediate of formula (χνιπ). I) Compounds, their N-oxide forms, pharmaceutically acceptable acid or basic addition salts, and their stereochemically isomeric forms can be used as class IV (CAMP-specific) phosphodiesterases (PDE) Effective inhibitor of heteroenzymes. CAMP (Adenoids 3'35'-monophosphate) is the main second messenger. Its degree of activity can affect the activity of specific cells through the activity of enzymes such as kinases. It is known that PDE IV can hydrolyze cAMP into the corresponding The inactive 5, _monad acid vinegar metabolite, therefore, inhibits the amount of cAMP in PDEiVf rego in specific cells, such as respiratory smooth muscle cells and a variety of inflammatory cells such as lymphocytes such as basophils, neutrophils, Erythrocytes, monocytes and obese cells, a variety of allergic, atopic and inflammatory diseases. Because the PDE IV concentration is greater than normal, the amount of mcAMp and the sensitivity of the affected cells to irritation (an example of this allergy) For the formation of, for example, excess histamine or eosinophils released from basophils and obese cells, this paper size applies the Chinese National Standard (CNS) A4 specification (2I0x (锖 Please read the precautions on the back before filling this page) Order

424Q3T A7 Printed by the Consumers' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs B7 V. Excess Peroxide Anion of the Invention (Ice). Accordingly, the compounds of the present invention having phosphodiesterase IV inhibitory properties can be used to reduce and / or treat allergic, atopic and inflammatory diseases. The functional effect of PDE IV inhibitors is, for example, relaxation of respiratory smooth muscle Effects, bronchiectasis, inhibition of platelet accumulation, and inhibition of leukocyte release. Examples of allergic diseases are bronchial asthma, cheilitis, purulent meningitis, contact dermatitis and wetness, irritating pools. Diarrhea, deshydroform eczema, anesthesia, vasculitis, vulvitis; examples of atopic diseases are dermatitis and moisturization, winterfeet, asthmatic allergic rhinitis; and Related pains are, for example, psoriasis and other hyperproliferative diseases. Accordingly, the present invention also relates to the use of a compound of formula (I) as defined above as a medicament, especially as a medicament for the treatment of asthma or as a medicament for the treatment of atopic diseases. Therefore, the compound of the present invention can be used to manufacture a medicament for the treatment of asthma or Atopic disease, more specifically atopic dermatitis. The PDE IV inhibitory activity of the compound of formula (I) can be tested by "inhibiting the baculovirus vector to recombine human monocytes in human insect cells. (MNL) type IVB phosphodiesterase" tests have confirmed that several living organisms Internal and in vitro tests can be used to confirm the effectiveness of compounds of formula (I) in the treatment of the above-mentioned allergic, atopic and inflammatory diseases. These tests are, for example, "in vitro guinea pig trachea bronchoconstriction", "in vivo guinea pigs" Bronchoconstriction of trachea &quot; and in vivo testing of edema caused by bacterioglycan in mouse ears &quot;. In addition, the compounds of the present invention have very low inhibitory activity on the group IIIII phosphodiesterase isoenzymes (cGMP-inhibitory family), specifically, inhibition (please read the precautions on the back before filling this page). Chinese National Standard (CNS) A4 specification (210X297 mm) 424087 A7 ________B7 V. Description of the invention (Y) PDE III leads to an increase in cAMp in the myocardium, which in turn affects the contractility of the heart and the relaxation of the heart. In the case of atopic and inflammatory diseases, it is obvious that there is no cardio-vascular effect. Therefore, the concentration of the compound of the present invention when inhibiting PDE IV is much lower than that when inhibiting pDE η, and its therapeutic use can be adjusted to avoid heart And vascular side effects. "PDE IV inhibitors known in this hard technique usually cause a negative gastrointestinal effect, but most of the compounds of the invention have only a few effects on the gastro-intestinal tract, which can be found in 'I rats Calorie emptiness of calorie meals has been confirmed by tests. The names of PDE III and IV in this article refer to the classification of J, a. Beavo and DH Reifsnyder, Tips Reviews, 1990 April, 150-i55 pages. '' Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling out this page) The compounds of this invention also have cytokinin inhibitory activity, cytokinin Any secreted polypeptide that can affect the function of other cells by adjusting the role of cells in the immune or inflammatory response. Examples of cytokinins are unicellular and lymphokine and can be produced by a variety of cells. For example, monocytokine is usually produced and secreted by monocytes, such as macrophages and / or monocytes, but many other cells can also produce monocytokines, such as natural killer cells, fibroblasts , Neutrophils, endothelial cells, brain stellate cells, bone marrow stromal cells, keratinocytes, and β-lymphocytes. Lymphocytes usually refer to those produced by lymphocytes. Examples of cytokinins include Leukolysin-καί), endolysin_2 (lL-2), endolysin-6 (IL-6), endolysin, 8 (jl-8), 〇: -Tumor Necros is ~ 1Ί ~ This paper size applies Chinese National Standards (CNS) Α4 size (2 丨 〇 × 297 public shame) 424087 A7 Employees' Cooperative Cooperative Printing Policy B7 of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of invention (W) Factor (a TNF ) L / S-Tumor Necrosis Factor {β TNF). The cytokinin that needs to be inhibited is a TNF. The excessive or uncontrolled production of TNF is related to the promotion or exacerbation of many diseases, including rheumatoid arthritis, rheumatism Spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms; septicemia, septic shock, endotoxin shock, Gram's septicemia, toxic shock, adult respiratory distress, brain type Malaria, chronic pulmonary inflammation, pneumoconiosis, pulmonary sarcoidosis, bone wasting, reperfusion injury, graft-versus-host response, allograft rejection, fever due to infection such as a cold and muscle pain, infection or Post-malignant cachexia, acquired post-immune dysfunction (AIDS) cachexia, AIDS, ARC (AIDS-related complex), formation of keloids, formation of scar tissue, Crohn's disease, ulcerative colitis or Reese syndrome (pyresis). The inhibitory activity of compounds of formula (I) on cytokinins, such as the inhibition of a TNF production, can be confirmed by in vitro testing of "production of cytokinins in human whole blood cultures". Inhibitory properties of cytokinin. The compounds of the present invention can be formulated into different pharmaceutical forms for medicinal purposes. When preparing the pharmaceutical composition of the present invention, an effective amount of the specific compound is a basic or acid addition salt form of the active ingredient. It is intimately mixed with a pharmaceutically acceptable carrier. Depending on the preparation form required for administration, these carriers can have various forms. These pharmaceutical compositions need to be in unit dosage form, which is more suitable for oral, rectal, topical, For transdermal, inhalation or parenteral injection, for example, when preparing a composition for oral dosage form, any pharmaceutical preparation can be used in the case of oral liquid preparations such as suspensions, sugars, chitosan and liquids (please (Read the notes on the back before filling out this page)

This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) A7 B7 V. Description of the invention (&gt; 7) Water; Main glycols, oils, alcohols, etc .; Agents, tablets and heart-shaped tablets can be used in solid carriers such as starch, sugars, mastics, lubricants, adhesives, disintegrating agents, etc. Due to their convenience, tablets and capsules represent the most advantageous oral dosage The unit form 4 in this case obviously uses a solid pharmaceutical carrier. For parenteral compositions, the carrier usually includes sterile water, at least for the most part, and may include other ingredients such as solubilizers. For example, a liquid for injection can be prepared in which the carrier contains saline, glucose solution, or a mixture of saline and glucose solution moxa. It can also be prepared as an injectable suspension, in which case a suitable liquid carrier, suspending agent, etc. can be used. In the composition suitable for transdermal application, the carrier may contain a penetration enhancer and / or a suitable wetting agent, if necessary, and in combination with a suitable small amount of natural additives, the additive will not cause any obvious damage to the skin. Adverse effects, the additive can promote the application to the skin and / or help to prepare the desired composition. These compositions can be administered in the same way, for example as a skin patch or as an ointment. As a suitable composition for topical application, it can include all the components usually used for topical application such as Emulsions, gelling agents, dressings, lotions, pastes, soft lean, oil poor, powders, etc. The composition can be applied via gas; cereals, such as propellants such as nitrogen, carbon dioxide, Freon, or not Propellant-containing agents such as canister sprays, droplets, emulsions, or semi-solids such as thickened compositions can be used via cotton balls. Specifically, semi-solid components such as ointments, emulsions, gelling agents, ointments and the like can be conveniently used. In order to enhance the solubility and / or stability of the compound of formula (I) in the pharmaceutical composition, α-, point-, or τ-cyclodextrin or its derivative, especially cyclodextrin substituted with a calcining group, should be used. For example 2 _ borrow propyl-stone cyclodextrin, the paper size suitable financial WSFTcNS) A4 ^ (210X297 ^ *) — ^ n —f ^ i _

-I-m I ------- (^ __ (Please read the notes on the back before filling out this page) Printed by the Employees 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 414087 A7 ____B7 5. Description of the invention (ΛP) Moreover, auxiliary solvents such as alcohols can also promote the solubility and / or stability of the compound of formula (I) in the pharmaceutical composition. The addition salts of the compounds of the present invention are obvious when preparing aqueous compositions. It is more suitable because of its increased water solubility. It is particularly suitable for formulating the above pharmaceutical composition into a unit dosage form for convenient use and uniform dosage. A dosage unit form refers to a separate unit on an object suitable as a unit dose. The unit contains a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, and the required pharmaceutical carrier. Examples of this dosage unit form are tablets (including scored or coated tablets), capsules, pills, Powder packaging, glutinous rice paper capsules, injection solutions or suspensions, etc., and their separated repeated amounts. The present invention also relates to a method for treating warm-blooded animals Disease states associated with abnormal fermentation or catalytic activity of PDE IV and / or disease states associated with physiologically injured excess cytokinins, especially allergic, atopic and inflammatory diseases, more specifically asthma Sexual and ectopic diseases, most specifically, ectopic diseases, the formula excludes a therapeutically effective dose of a compound of formula (I) or its N-oxide form, a pharmaceutically acceptable acid or base Addition salts or their stereochemically isomeric forms, and mixed with pharmaceutical acceptable carriers. Generally speaking, the effective daily dose is from 0.01 mg / kg to 10 mg / kg body weight, From 0.04 mg / kg to 5 mg / kg body weight is more preferred. It is clear that the effective daily dose can be reduced or increased according to the response of the treated individual and / or according to the evaluation of the prescriber of the compound of the present invention. The effective dose is for reference only, and is not intended to limit the scope or use of the present invention. The following examples are intended to illustrate the present invention and not to limit its scope. 30- This paper size applies to China National Standards (CNS) A4 regulations (2IOX 297 mm) (read first read the note and then fill in the back of this page) book

L Printed by Shelley Consumer Cooperation, Central Standards Bureau, Ministry of Economic Affairs ^ 24 0 1 at _____B7 _V. Description of the Invention (#) Experiments Some compounds of formula (I) and some intermediates contain stereoisomeric centers. In these cases, The system separates the racemate into the palmar isomers. The stereochemically isomeric form that is separated first is called "A" and the latter is called "B", without further specifying the actual stereochemical configuration. Example of preparing intermediate A.1 Under a flow of 1 ^ 2, a solution of benzyltrimethylammonium dichloroiodide (78 g) in THF (2 50 ml) was added to 1 .- [3- (cyclopentane) under agitation. Oxy) -4-methoxyphenyl] ethanone (26.3 g) in a mixture of THF (250 ml), the resulting reaction mixture was stirred at RT for 16 hours, the solvent was evaporated and the residue was re-used Dissolved in ether (300 mL), this mixture was added dropwise to a 5% Na2S204 solution (400 mL), and the aqueous layer was extracted twice with ether (100 mL), and the combined organic layers were extracted twice with water (500 mL). , Dried over MgS04, filtered and the solvent was evaporated, the crude oil was crystallized from hexane, Shen Dianwu was filtered, washed with hexane and dried to produce 11 g of 2-chloro-1-[3- (cyclopentyloxy) -4-methoxybenzyl] ethyl. Ketone, the filtrate was evaporated and the residue was crystallized from hexane, the precipitate was filtered and dried to yield 7.4 g (24.6%) of '2 light shift (5 Caiyu. ) 土 i 氧 终} and ϋ. Add sodium bis (trimethylsilyl) amine (5 ml) to 1,3-dihydro-2Η-imidazol-2-one (0.84 g) in N while stirring under 1 ^ 2 flow and cooling in an ice bath. , N-Dimethylformamide (50 ml), and the reaction mixture was stirred for 30 minutes. (Please read the precautions on the back before filling this page) The size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (2LOX297 mm.) 4 ° ^ 〇δ «a? '_____ Β7_ Five' Invention Description (Μ) Intermediate 1 (2.69 g) was added portionwise and the resulting reaction mixture was stirred at room temperature for 16 hours, then stirred at 50 ° C for 2 hours, and in fluorenyl isobutyl ketone / water (200 ml / 50 ml) The reaction mixture was stirred and evaporated, the solvent was evaporated, fluorenyl isobutyl ketone (100 milliwell) was added and azeotroped on a rotary evaporator, and the mixture was purified on silica gel by column chromatography (eluent: CH2C12 / (CH30H / NH3) 97/3), collect the required fractions and evaporate the solvent. The white solid was stirred in DIPE, filtered, washed with DIPE and dried, yielding 0.4 g (12.6%) 1- [2- [3- ( Cyclopentyloxy) -4-methoxyphenyl] -2-ketoethyl] -1,3-dihydro-2H-imid-2- (isolate 2; melting point 201.PC). Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs at% flow and -78 ° C, stirring the mixture of intermediate 2 (1 g) in THF (50 ml), and adding phenyl lithium (3.52 ml; 1.8M) dropwise The solution was in cyclohexane / ether 70/30) and the mixture was stirred at -78 ° C for 30 minutes. The mixture was allowed to warm to room temperature and continued to stir for 1 hour. Additional phenyl ether was added dropwise at room temperature. (1.5 ml) and the mixture was stirred for another 2 hours, the mixture was stirred and refluxed for 1 hour, then cooled in an ice bath and saturated NH4C1 solution was added to stop the reaction. This mixture was extracted three times with .CH2C12 (100 ml), The separated organic layer was dried over MgS04, filtered, and the solvent was evaporated. The residue was purified on silica gel using short column chromatography (eluent: ch2ci2 / ch3oh / (ch3oh / NH3) 90/5/5), and the pure And the solvent was evaporated, the residue was ground in DIPE, and the precipitate was filtered; the object was washed with DIPE and dried, yielding 0.2 g (16%) (soil) -1- [2- [3- (cyclohexyl oxide) Group) -4-methoxyphenyl] -2-hydroxy-2-phenethyl] -1,3-dihydro-2H-imidazol-2-one (Intermediate 3). .32 ~ This paper size applies to China National Standard (CNS) M specifications (210X297 mm)

4I408T 丨 Supplement A7 Patent Application No. 85103446-Kuc ratcnt Appm, -t \ a-; O iuj44tr Amendment Sheet-Appendix (3) Amended Page of the Chinese Specification ~ Enel. ΓΙΙΙ) (Positive and suitable) ---------- '' (Amended &amp; Submitted on March &gt; |, 2000) Example A.2 The 1- (diphenylmethyl) -2- A solution of imidazolinone (10 g) and sodium hydroxide (100 mg) in methanol (50 ml) and formaldehyde (50 ml; 37%) was stirred for 6 hours. The solvent was evaporated and the residue was dissolved in water. Extracted 3 times. The separated organic layer was dried (MgS04), filtered and the solvent was evaporated. The residue was stirred in ether, filtered and dried to give 9.7 g (86.6%) of the product. A portion of the sample (2.5 g) was extracted from ethyl acetate. The crystals were recrystallized, and the precipitate was filtered and dried to give 0.49 g of 1- (diphenylmethyl) -3- (hydroxymethyl) -2-imidazolinone (Intermediate 4; melting point 133.5 ° C). A mixture of intermediate 4 (8.4 g) and tribenzylphosphonium bromide (10.3 g) in B (100 ml) was stirred and refluxed for 1 hour. After the solvent was evaporated, the residue was dissolved in toluene and boiled to precipitate. The product was filtered and dried to yield 17.5 g (96.2 ° /.) Of triphenyl bromide [3- (diphenylmethyl) -2,3-dihydro-2-one-l-1H-imidazole-1-methyl] Town (intermediate 5). V. Description of the invention (谙 Read the precautions on the back before writing ¥.)-Install the printed example of the employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A.3 Use bromobenzene (18.M grams), magnesium spinner (2.9 G), iodine (catalyst amount) and aluminum (catalyst amount) to form a Gngnard reagent in THF (105 ml), and a solution of bromine in THF (100 ml) was added dropwise to the magnesium bar under a stream of ^^ 2 Stir the solution with iodine in THF (5 ml), stir and heat the reaction mixture. After all the bromine is added, stir and reflux the reaction mixture for 1 hour. Cool the mixture in an ice bath, dropwise at 0 ° C. Add a solution of 3- (cyclopentyloxy) -4-methoxybenzaldehyde (22.03 g) in THF (80 ml), stir the reaction mixture at room temperature for 2 hours, and then cool to -33- Applicable to China National Standard (CNS) A4 specification (210X297 mm)

-^ m:-I

J Α7 Β7 Printed by the Consumer Cooperative of the Central Operating Bureau of the Ministry of Economic Affairs. 5. Description of the invention (h) 0 ° C. Add saturated NH4C1 solution (200 ml) dropwise and extract the mixture twice with CH2C 2 (100 ml). The separated organic layer was dried (MgS04), filtered and the solvent was evaporated, yielding 29.3 g (98%) (±) -3- (cyclopentyloxy) -4-methoxy-phenylbenzyl alcohol ( Intermediate 6). A mixture of intermediate 6 (29.3 g) and magnesium (IV) oxide (85 g) in CHz Chp OO ml) was stirred at room temperature for 48 hours. The reaction mixture was filtered through hard soil and the lye was evaporated to leave a residue. Was recrystallized from DIPE, the precipitate was filtered, washed with DIPE and dried to give 14 g (48%) of [3- (cyclopentyloxy) -4-fluorenylphenyl] phenylmethanone (Intermediate 7; (Surprising 76.4 ° C). Example A.4 A solution of sodium bis (trimethylsilyl) amine in THF (55 ml; 2 mole concentration) was added to 2-keto-imidazolidine-ethyl carboxylate (1.58 G) in a mixture of THF (150 ml), with continuous stirring for 1 hour, the mixture was cooled and 2-bromo- (3,4-dimethoxyphenyl) ethane in THF (50 ml) was added Ketone (2.6 g). The mixture was stirred for 1 hour and then decomposed with water. The aqueous layer was extracted with CHaCh and the organic layer was dried (MgS04), filtered and evaporated. The residue was purified on silica gel by column chromatography. (Eluent: CH / h / CtbOH 98/2), the pure eluate was collected and the solvent was evaporated, and the residue was recrystallized from ethyl acetate, dried and dried to obtain 1.57 g (46 · 7%) ) 3- [2- (3,4-dimethoxybenzyl) -2-ketoethyl] -2-keto-1-imidazolidine-1-carboxylic acid ethyl ester (Intermediate 8; melting point 133.9 °). ° ~ 34 ~ This paper size is applicable to China National Standard (CNS) Α4 size (210X 297mm) (Please read the notes on the back before filling this page) Order 414087 a? '__87_ __________ ------- &quot; &quot; r. Description () _ melons; M

i 补 ι 1 J •, a — — a mixture of intermediate 8 (0.5 g) and potassium carbonate (0.5 g) in ethanol (50 ml) was stirred and refluxed for 30 minutes, then cooled and poured into water, using Extracted 3 times with CH2C12. The organic layer was separated and the solvent was evaporated. The residue was purified on silica gel by column chromatography (eluent: CH 2 C 丨 2 / C Η 3 〇Η 95/5), and the pure dissolution was collected. The solvent was evaporated and the residue was recrystallized from CH3CN. After filtration and drying, L62 g (37.5%) of 1- [2- (3,4-dimethoxyphenyl) -2-one ethyl was obtained. ] -2-Imidazolidone (Intermediate 9; Melting point. 16 6.6 ° C). According to the procedures described in Example A, lc, (±) -1- [2- (3,4-dimethyllactylphenyl) -2 -yl-2-epiethyl] -2 -taste-stewed steel (Intermediate 10; melting point 154.4 ° C). Preparation formula (Π Compound Example B.1 —1 丨 — 丨 ·, (· Step 1 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, and add sulfurous thoron gas (0.5 g) dropwise to the intermediate at room temperature. 3 (1 g) in CH2Cl2 (10 ml). Stir the reaction mixture at 30 ° C for 3 hours, then evaporate the solvent to evaporate the residue with toluene. Dissolve the residue in methane and use K2C03. (10% solution) was washed, the organic layer was dried over MgS04, filtered and evaporated under reduced pressure to obtain 0.8 g of crude 1- [2- [3-cyclopentyloxy) -4-methoxyphenyl] vinyl ] -1,3-dihydro-2H-imidazolone (Compound 1; E / Z isomer ratio = 60/40). Compound (I) was further purified and separated into its pure E and Z on a silicone tube. Isomers, (eluent: CH2C 丨 2 / MeOH98 / 2), producing 50 mg ~ 35 ~ This paper size applies Chinese National Standards (CNS) A4 specifications (210X25 ^ gong) 4 24087 — A7 ______B7 V. Description of the invention () Printed by E · 1- [2- [3-Cyclopentyloxy] -4-methoxyphenyl] ethynyl] -1,3-digas, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs _ 2H-imidazolidone (Compound 2) and 50 mg of Zl- [2- [3-cyclopentyloxy] -4-methyllactylbenzyl] ethoxy] dihydro-2H-weitu butterfly (Compound 3) . Step 2 Stir the solution of Intermediate 3 (1g) and triethylsilane (1ml) in CH2C12 (00ml) at 0-3 ° C. Add trifluoroacetic acid (0_68ml) to CH2C12 (50ml) dropwise. Ml) solution for 2 hours, the resulting reaction mixture was allowed to warm to room temperature, and then stirred for 48 hours. The solution was neutralized with solid Na2C03, filtered and the filtrate was evaporated. The residue was purified via silica gel in a glass filter (Eluent: CH2C12 / CH30H 90/10). Collect the pure eluate and evaporate the solvent to recrystallize the residue from CH3CN. The precipitate was filtered, washed with CH3CN and DIPE, and then dried to yield 0.4 g (41.6 %) (£) -1- [2- (3-Cyclopentyloxy |) -4-methoxyphenyl] -2-phenylvinyl] · 1,3-dihydro-2H-amizole-2 -Ming (Compound 2). Example B.2 a) Stir a mixture of sodium argon (2.88 g; 50%) in THF (250 ml) at room temperature under a flow of 1 ^ 2, and add (diethyllinyl) ethyl picanoate dropwise. (13.45 g) 4 Keep the temperature below 15 ° C, stir the reaction mixture for 30 minutes, add the intermediate 2 (6.32 g) in portions, continue stirring for 1 hour, cool the reaction mixture in an ice bath and use NH4C1 solution Decompose and extract the aqueous layer 3 times with CH2C12. The separated organic layer is dried (M g S 0 4), filtered; the solvent is evaporated, and the residue is purified on the broken gel by column chromatography (eluent) ： CH2C12 / C2H50H 95/5), collect pure solution ~ 36 ~ This paper scale uses China National Standards (CNS) Α4 is present (210X297) 嫠 {Please read the precautions on the back before ^ Smart copy 1- Bookbinding-'Table ----------------5. Description of the invention (π) Α7 Β7 Separate the fractions and evaporate the solvent to recrystallize the residue from CHsCN. After the precipitate was filtered and dried, 1.19 g (15.4%) of (E) -3- (cyclopentyloxy) -zhao-[(2,3-dihydro-2-keto-1H-imidazole-1) was obtained. -Yl) -methylene] _4-methoxybenzyl ethyl propionate (chemically 4; melting point 164.TC,), the filtrate was evaporated to produce 10 g (Z) -3- (cyclofluorenyloxy) -cold-[(2,3-dihydrod-keto-lH-imidazolium -Methyl) _Methylene] -4-methoxyphenylpropionate (Du Yinhu, a co-consumer of the Central Standards Bureau of the Ministry of Compound Economy, prepared in a similar way: (E) -3,4-dimethyl Oxy-cold-[(2-keto-1-imidazolidinyl) methylene] benzylpropionitrile (compound 6). B) Stir compound 5 (g) in ethanol (50 ml) at room temperature. To the mixture, sodium hydroxide (50 ml; 1 equivalent concentration) was added dropwise, and the stirring was continued for 16 hours. The solvent was evaporated, the residue was dissolved in water and washed 3 times with CH2C12, and the aqueous layer was acidified with 1 equivalent concentration HC1 and used. CH / U extraction 3 times, the organic layer was separated, dried (MgS04), filtered and the solvent was evaporated, and the residue was purified on a gel using column chromatography (eluent: CH2C12 / CH30H 95/5), The pure fractions were collected and the solvent was evaporated. The residue was recrystallized from CH3CN. After filtering and drying the precipitate, 2.2 g (36.1%) of (Z) -3- (cyclopentyloxy) -J8- [ (2,3-dihydro-2.keto-lH-imidazole-l-yl ) -Methylene] -4-methoxyphenylpropionic acid (compound 7; melting point 193.7 ° C). -37 ~ This paper uses China National Standards (CNS> A4 size (210x297)) ------- (Please read the notes on the back before filling this page) Order 424087 A7 B7 Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 5. Description of the invention () Example B.3 The mixture of intermediate 10 (2.04 g) in THF (120 ml) and argon acid (6 ml; equivalent concentration) was stirred and refluxed for 8 hours. The reaction mixture was cooled, basified with K:! CO solution and the solvent was evaporated, the residue was dissolved in water and extracted with ch2ci2, and the separated organic layer was dried (MgSOd, filtered and the solvent was evaporated, Purify the residue on silica gel by column chromatography (eluent: 0.5% ammonium acetate in water / (: 1 &quot; 13〇 "99.5 / 0.5), collect the required fractions and evaporate the solvent. The residue was stirred in DIPE, filtered and dried, yielding 0.38 g (11.7%) of 1- [2- (3,4--methyllactylphenyl) -2-phenylethenyl] -2-flavor Same as S (Compound 8: melting point 55.3 ° C). Example B.4, a mixture of intermediate 10 (2 g) and acetic anhydride (20 ml) was stirred and ··, The reflux time was 6 hours. The solvent was evaporated and toluene was added twice and evaporated again. The residue was purified on silica gel by column chromatography (eluent: CH2C12 / CH30H 98/2), and the pure eluate was collected. The solvent was evaporated to produce 1.2 g of product. This part was purified on silica gel using HPLC (eluent: CH2C12 / CH30H 98/2). The pure eluate was collected and the solvent was evaporated to produce 1.02 g of product. Crystallized from ethyl acetate, and the precipitate was filtered and dried to give 0.53 g (24.8%) of 1-ethylfluorenyl-3- [2- (3,4-monomethoxymethylene) -2-fengylethyl Diluted] -2 · Smell bite S (Compound 9) 〇

This paper size applies to Chinese national standards (CNS M4 specification (210X297 mm) Please read the precautions on the back before filling out this page) Binding 1 · Order 424087 A7 B7 V. Description of the invention ()

.iL Supplement η Printed by the Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumer Cooperative Cooperative Example B.5 Stir THF (200 ml) and add sodium hydride (0.84 g; 50%) at room temperature and> 12 flow, and add intermediates in portions 5 (6.05 g), continuous stirring for 2.5 hours, intermediate 7 (2.96 g) was added and the reaction mixture was stirred for 16 hours, the mixture was cooled in an ice bath and decomposed with NH4CI aqueous solution, and then extracted 3 times with ether, separated The organic layer was dried (MgS04), filtered, and the solvent was evaporated. The residue was purified on silica using column chromatography (eluent · Η: Η2α2 / (: Η3ΟΗ 99/1) and collected the required The fraction was evaporated and the solvent was evaporated to produce 6 g of product. This fraction was purified on silica gel by column chromatography (eluent: CH2C12 / CH30H 99.9 / 0.1). The pure fraction was collected and the solvent was evaporated to yield 1.2. Grams of dissociation 1 and 1 -1 grams of dissociation 2, and dissociation 1 is stirred, filtered and dried in DIPE, yielding 0.82 g (15%) (E) -1- [2- [3- (cyclopentyloxy) -4-methoxyphenylb 2-phenylvinyl] -3 · (dibenzylmethyl) -1,3:, dihydro-2 ^ 1-imidazol-2-one (compound 10), Fraction 2 was stirred in DIPE, filtered, and dried to yield 0.57 g (10.5%) of (2) -1- [2- [3- (cyclopentyloxy) -4-methoxyphenyl] · 2-benzene Ethylethoxy] -3- (diphenylmethyl) -1,3-dihydro-2H-imidazol-2 · * _ (Compound 11). Prepared in a similar manner: (Z) -1- [2- [3- (Cyclopentyloxy) -4-methoxyphenyl] -1-propenyldiphenylmethyl) -2H-imidazol-2-one (Compound 12); (E)- l- [2- [3- (Cyclomethoxy) -4-methoxyphenyl] -1-propenyl] -3_ (dibenzylmethyl) -2H-imidazole-2 · one (Compound 13). -39- This paper uses China National Standard (CNS) A4 scale (210 X 297 mm) (Please read the precautions on the back before clicking this page)

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-V. Description of the Invention (β) c. Pharmacological Youth Case J1] C 1: Human monocyte lymphocytes that inhibit the production of baculovirus-like disease in insect cells and recombine the taste MNL) IV Type B Phosphodiester 醢 In vitro test system is used to detect the inhibitory effect of IV Type B phosphodiesterase on recombined human MNL in order to evaluate the allergic and heterotopic properties of the compounds of the present invention. Disease alleviation and / or therapeutic effect. 72 hours after infection with recombined baculovirus, insect cells were collected and made into 500 g pellets for 5 minutes. Cells were lysed in 10 ml of lysate-buffer containing 20 mM Tns and 10 mM EGTA , 2 mM Na2EDTA, 1% Triton-X-10〇, 1 mM Na3V04, 10 mM NaF, 2 μg / ml Leupeptin, Peptin and Aprotinin , 0.3 μg / ml benzylamidine and 1000 μg / ml TPCK pH 7.5, after 5 minutes on ice, at 4. (: The lysed cells were centrifuged at 400 ° rpm for 15 minutes, and the resulting clear solution was filtered through a 0.45 micron filter paper (MiHipore) and added to TBS buffer (50 mM Tds, 150 mM NaCl pH7, 4). Subsequently, the clear solution containing IV B-type squelate diesterase (PDE) was added to a 5 ml anti-resistance gel column, and 5 ml of 100 millimolar aminoglycol pH 3.5 was first used. Activate and equilibrate with 20 ml of 50 mM Tns and 150 mM NaCl pH 7.4. After washing the column with equilibration buffer, PDE IV is dissolved into 1.5 ml of fractions and contains 37.5 microliters of 1 Molar Tris. Dissolve the lysate at 20 mol concentration Tns, 2 mol concentration Na2EDTA, and 400 mol concentration NaCl ρ7.5 · 5 overnight and test the PDEIV activity at pH8. The paper standard is applicable to Chinese countries. Standard (CNS) A4 specification (2.10X297 mm) h, 4 ------ order (please read the notes on the back before filling in this education) Printed by the Central Samples Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 4240B Α7 1 ________B7 5. Description of the invention (yes)

Confirm on a Blot (anti-FLAG-M?), Combine the active fractions, add 10% glycerol and store at -70 ° C. The incubation mixture (pH 8) (200 microliters) contains 20 millimolar Tris, millimolar magnesium sulfate, 0.8 micromolar 3H-cAMP (310 milliCi / mmol) and type IV phosphodiesterase, The amount depends on the fermentation activity, and the protein concentration used is 37. (: During the incubation period of up to 10 minutes, the phosphodiesterase activity can show a linear increase, and less than 10% of the initial matrix is hydrolyzed. When testing the effect of different compounds on phosphodiesterase activity, cAMP-free The medium is compound or its carrier (DMSO-1% final concentration). 'Incubation lasts 5 minutes and the fermentation reaction is started. It is started by adding 3h-cAMP for 10 minutes and then transferred to a trace amount in a 100 ° C water bath. The titration plate lasted 5 minutes. After cooling to room temperature, alkaline phosphatase (0.25 μg / ml) was added and the mixture was incubated at 37 ° C for 20 minutes. Then 100 μL of the mixture was added to GF-B. Filter paper microtiter plate (MilHpore) and fill with 300 microliters of DEAE-Sephadex-A25 suspension, wash the plate 3 times with 75 microliters of 20 millimolar Tris pH 7.5, collect the filtrate and flash toad in Packard Top Count Counting in a counter. The inhibitory effect of the compound of the present invention on the recombined human MNL IV type B phosphodiesterase is measured at different compound concentrations, and the IC50 value is calculated graphically from the inhibition value thus obtained (represented by M ), The IC5G value of Compounds 2, 4 and 12 is less than 1x10_6M, and the IC50 value of other compounds is greater than or equal to 丨 x10_6M 〇 This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) {Please read the note on the back Matters refill this page}

1T 42.4 Secret 1 a? __________ B7 V. Description of the invention (where) The edema caused by bacterial glycosaminoglycans in the ears of mice will be injected systemically with bacterial glucosaminoglycan T500 in normal uninduced mice to make blood vessels Increased penetrability, resulting in extravasation and edema of the limbs + Bacterial glucosan is injected with blue dye, and ears turn blue is edema ^ The most obvious feature of the response ~ 24-26 grams of male Swiss mice are administered orally The test compound or solvent dissolved in PEG, 200 at different concentrations was taken in advance. After 1 hour, the mice were injected subcutaneously with 12 mg / ml of bacterioglycan butan in a volume of 0.1 liters with a body weight of 10 grams. 500 and 2.6 mg / ml protamine sky blue dye isotonic saline solution. After 1 hour and 45 minutes, the animals were killed with ether and the ears were removed. According to Van Wauwe and

The method disclosed by Goossens (Drug Dev. Res. 1986, 8, 213-218) was used to extract and quantify the outer paint dyes. Dye extravasation is identified by the blueness value, which is defined as the concentration of the dye extracted on the ears. The background blueness value is determined from the saline solution containing only bacterioglycan T500 and blue dye. Injected into a group of mice and calculated their average blueness values. Table 1 lists the test compounds' inhibition of dye extravasation compared to the background extravasation of the dye when the test + compound is administered at a dose of 0.5 mg / kg. percentage. (Please read the notes on the back before filling this page)

A. Order the consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs. Printed by the company. Table 1 Compound number inhibition% 2 15.5 4 25.9 7 49.9 ~ 42 ~ This paper is applicable to China National Standards (CNS) specifications (2 丨 0; &lt; 297) %) 42408ϊ 5. Description of the invention (from /) Α7 __B7 Compound number inhibition% 8 17.9 9 11.1 10 40.1 11 19.3 Consumers' cooperation of the Central Standards Bureau of the Ministry of Economic Affairs printed P. Composition Examples The following formulation system examples illustrate the invention according to the invention Typical pharmaceutical composition for systemic or topical application to animals or humans. The "active ingredient" (AI) used in these examples refers to the compound of formula (I) or its pharmaceutically acceptable addition salts. Example D.1: Film-Coated Tablets Preparation of Tablet Cores 100 grams of AI, 570 grams of lactose, and 200 grams of starch are thoroughly mixed, and then wet with a solution of 5 grams of sodium lauryl sulfate and 10 grams of polyvinylpyrrolidone in about 200 milliliters of water to wet the powder The mixture was sieved, dried and sieved again, then 100 grams of microcrystalline cellulose and 15 grams of hydrogenated vegetable oil were added, and the whole was thoroughly mixed and compressed into tablets to obtain 10,000 tablets, each The tablet contains 10 mg of the active ingredient. Coating Add 5 g of ethyl cellulose in 150 ml of digasmethane to a solution of g methyl cellulose in 75. ml of denatured ethanol, then add 75 ml of dichloromethane and 2.5 liters of I, 2,3-propanetriol, 10 grams of polyethylene glycol This paper is sized to the national standard _ (CNS) A4 (210 X 297 mm) (Please read the precautions on the back first (Fill in this page) Λ 衣

U Consumption cooperation between employees of the Central Standards Bureau of the Ministry of Economic Affairs Du Yinquan 1 A7 ____ B7 V. Description of the invention (along) Melt and dissolve in 75 ml of digas methane, add the latter solution to the former liquid, and then add 2.5 Grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone, and 30 ml of concentrated suspension were homogenized and the tablets were core coated with the thus obtained mixture in a coating apparatus. Example D.2: 2% rolling is added to the double sheath of 75 mg of stearyl alcohol, 2 mg of cetyl alcohol, 20 mg of sorbitan monostearate and 10 mg of isopropyl myristate In a container and heat until the mixture is completely melted, add this mixture to a mixture of pure water, 200 mg of propylene glycol, and 15 mg of polycondensed sorbitol oleate 60 prepared separately at a temperature of 70 to 75 ° C and make it into a homogenizer. Liquid 'allowed the resulting emulsion to cool below 25 ° C and continue mixing, then 20 mg of AI, 1 mg of polycondensed sorbitol oleate 80 and pure water (solution and 2 mg of anhydrous sodium sulfite) A solution of water was added to the emulsion, and a cream containing 1 g of A · ί. Was homogenized and filled into a suitable tube. Example D. 3: 2% fraction; gelatinized at 200 mg hydroxypropyl- Add 20 mg of A.I. to a solution of cyclodextrin in pure water and stir at the same time. Add hydrochloric acid until completely dissolved, then add sodium hydroxide until pH 6.0, and add this solution to 0 mg with stirring. Carrageenan PJ in a suspension of 50 mg of propylene glycol. The mixture was heated to 50. (:, allowed to cool to about 35. (: At the same time, 50 mg of 95% (v / v) ethanol was added, the remaining gram of pure water was added and the mixture was mixed until homogeneous. The dimensions are applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the precautions on the back before filling this page)

* 1T

L A7 __B7 V. Description of the invention (Xue 3) Example D.4: 2% topical cream In a solution of 200 mg of light propyl / 5-cyclodextrin in pure water was added 200 mg of AI while stirring, Add hydrogen acid until completely dissolved, then add sodium hydroxide until pH 6.0, add 50 mg of glycerin and 35 g of polycondensed sorbitol oleate 60 under stirring, and heat the mixture to 70 ° C. Slow the resulting mixture Add to 100 mg of mineral oil, 20 mg of stearyl alcohol, 20 mg of cetyl alcohol, 20 mg of glyceryl monostearate and 15 mg of sorbic acid at 70 ° C. Cool to low After 25 ° C, add the remaining 1 g of pure water and mix the mixture until homogeneous. Example D.5: 2% liposome formulation. A mixture of 10 grams of squamous fat SI and 1 grams of cholesterol was stirred in 7.5 grams of ethanol and heated at 40 ° C to completely dissolve. Dissolve 2 grams of AI particles in pure water, slowly add the ethanol solution to the aqueous solution within one minute of the homogenization process, add 15 grams of hydroxypropyl methyl cellulose in pure water and stir until fully swollen. 1 equivalent of sodium nitroxide The resulting solution was adjusted to pH 5.0 and diluted with the remaining 100 g of pure water m ° '!-I-I ---- ---- ^-----ϋ-I n., 1τ (Please read the notes on the back before filling out this page) Printed by the Central Government Bureau of the Ministry of Economic Affairs on consumer cooperation

5- T 标 One Standard-Home Country-Middle Use-Suitable Size Paper Yihe

Ns Class I Rule I cm

Claims (1)

Patent application scope: A8B8C8D8 No. 85103446 Patent application ROC Patent Appln. No. 85103446 Amended application scope Chinese text-Attachment (1) Amended Claims in Chinese-(Enel. Ϊ) (March 89 &gt; 丨 Send) (Submitted on March), 2000) A compound of the formula 0) (Please read the precautions on the back of It before filling out this page) K ------ President of the Intellectual Property Bureau of the Ministry of Economy Formula or basic addition salts and their stereochemically isomeric forms, in which: R1 and R2 are independently of each other (V6 alkyl or 03-6 cycloalkyl; R3 is hydrogen; R4 is C, -6 alkyl, via Cyano, carboxyl or (V6 alkoxycarbonyl substituted CV6 halo, or benzyl; envy is hydrogen; Y is a direct bond; -AB- is a divalent group of the formula: -CH = CH- or -CH2- CH2-; L is hydrogen, (V6 alkylcarbonyl or CV6 alkyl substituted by phenyl. -46- J85IJ6-RE-CLAIM-CH Order --------- line ί This paper size is applicable to China Standard (CNS) A4 specification (210 * 297 mm) 4 ^ 081 B8 C8 D8 _ 1 ~-_____ VI. Patent application scope 2 · Compound according to item 1 of the patent application scope, where R1 is a pit group or 〇3_6 ring Alkyl and 胪 is c] 6 alkyl. 3. Compounds according to item 1 or 2 of the scope of the patent application, where L is ^ or Ct-δ. Group 4. Compounds according to item 1 or 2 of the scope of patent application, Where ^ | is _CHCH-of 5. The compound according to item 1 of the scope of the patent application, wherein the compound is .. 1-cyclopentyloxy) -4-methoxyphenyl-2-phenylethynyl] -1,3- Dihydro-2H-imidazol-2-one; 3- (cyclopentyloxy) -but-[(2, 3-dihydro-2-benzyl-1H-imidosal-1-yl) methylene] -4 -Ethyl methoxyphenylpropionate, 1 ~ [2- [3- (cyclopentyloxy) -4_methoxyphenyl] -1-propenyl] (diphenylfluorenyl) -2H -Imidazol-2-one; its N-oxide form, pharmaceutically acceptable acid or basic addition salts, and its stereochemically isomeric forms. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (Jing Read the precautions on the back before filling in the truth,) 6.—A pharmaceutical composition for treating a disease state related to abnormal fermentation or catalytic activity of PDE IV and a disease state related to excessive physiological damage to cytokinin , Which includes a pharmaceutically acceptable carrier, and a therapeutically effective amount of the compound according to the scope of the patent application as the active ingredient. -47- ^ Paper size applies to China's national standard (CNS) A4 specification (210X297 ^ ) 424087 Warp Printed by the Ministry of Intellectual Property Bureau's Consumer Cooperatives 6. Application for Patent Scope 7, Compound according to Item 1 of Patent Application Scope, which is used to treat disease states related to abnormal fermentation or catalytic activity of PDE IV and cytokinin The use of drugs for disease states associated with excessive physical injury. 8. — A method for preparing a compound according to the scope of the patent application, characterized in that: a) an intermediate of the formula Among them, R1 to R5, Y, -AB- and L are the same as those defined in the first item of the patent application. 'In the reaction inert solvent and in the presence of an acid, or using methanesulfonium gas or a functional derivative thereof in the presence of a base. Dehydration;. B) the Wit tig reagent-5 XX (QHjhP ^ CH-Y — N NL '(IV-a) A —B 、 -48-This paper size applies the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) ------------- {Send -------- Order --------- Line 1 I (Please read the precautions on the back first (Fill in this page again) Sixth, the scope of patent application ^ Y, and -AB · are the same as those of the Chinese patent, and X is a suitable ions and L. is the same machine but not hydrogen. The formula will be similar to the formula ([ Va) and the following formula Wherein, R1 to R4 are the same as those defined in the patent application. They are reacted in a reaction inert solvent and in the presence of a suitable base, so an intermediate of the following formula is formed. R4 R3 C = .C- Y—n 0 person BU one L_ (Ia) AB C) will be the following formula of Wittig reagent R3 0 person 'X * (C6H5) 3P + -CH-Y—N NG (IV * b) AB ________ --___ ^ ^ -------Order --------- Line f-(Please read the notes on the back before filling out this page) Where R5, Y, and -AB- are the same as defined in the first patent application, X is a suitable counter ion and G is a suitable protecting group, or a phosphonium ester similar to formula (IV-b) is inert in the reaction Solvents and suitable bases -49,-This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 public love) R-0 R'O R3 R &quot; 〇 R1042408T § D8 VI. In the presence of the scope of the patent application, it reacts with the intermediate of formula (II) and then removes the protecting group, so the compound of the following formula is obtained: R4 R5 1! C = C- Y-NN-H (Ib) A_B d) Put the Wit tig reagent R4 CH-P + (C6H5) 3X · 00 of the following formula in which R1 to R4 are the same as defined in the first item of the patent application and X is a suitable counter ion, or will be similar to the formula ( (V), winter phosphonic acid and the intermediate of the following formula? X r5-C- y -n NL '(Vl-a) it A —B where R5 and -AB- are the same as those defined in the first patent application, γ It is a C | · 3 alkyldiyl group and L 'is the same as L but not argon. It reacts in the presence of a reaction inert solvent and in the presence of a suitable test, so a compound of the following formula is formed. This paper applies Chinese standards (CNS) ) A4 size (210 X 297 mm) n I --------- ί Agricultural ...------ Order --------- line, I (Please read the note on the back first (Please fill in this page for matters) R 'Rs C—C- Y'—N XN—L * (I * aO A8 B8 C8 D8 person. A —B e) The formula (VRWhtig reagent or scaly vinegar similar to the formula with the following formula &lt; Intermediate 0 \\ R -C- rN ng (Vi-b) AB where R and-are the same as defined in the application for item ^, γι is a C | .3 alkyldiyl group and g is a suitable protecting group, in a reaction inert solvent And react in the presence of a suitable base, and then remove the protective group, so a compound of the following formula is formed (please read the precautions on the back before filling in clothing f) Order R3 R4 R5 t 1 Y'—XN-H (IH) Negative t A—B Wisdom of the Ministry of Economic Affairs i. Consumption Cooperation of Employees Du Du 0 and if necessary, make the compound of formula (i_b) and formula W3_L, (XIV) reagent In the reaction, W3 is a reactive release group and L 'is the same as L but not argon as defined in item 丨 of the patent application range. The compounds of the formula (1) are converted into each other, so the compounds of the formula (Ia) are obtained: It can be treated with an acid to convert a compound of formula (I) into an acid addition salt, or treated with a base to convert a compound of formula (I) into a test addition salt, or conversely, it can be treated with an alkali to convert an acid addition salt Converted to free state base, or treated with acid to convert basic addition salt to free state acid; and if necessary, can prepare its N-oxide and / or stereochemically isomeric form 3 -51.- This paper size Applicable to Zhongluxian Family Standard · (_CNS) A4 Specification (210X297mm) 4I408T 丨 Supplement A7 Zhuo Hao Application No. 85103446-Kuc ratcnt Appm, -t \ a-; O iuj44tr Application Form Correction Sheet-Attachment (3) ） Amended Page of the Chinese Specification ~ Enel. ΓΙΙΙ) 1 Min S Fei Cang Zheng 'and appropriate) ---------- "(A mended & Submitted on March &gt; |, 2000) Example A.2 1- (Diphenylmethyl) -2-imidazolinone (10 g) and sodium hydroxide (100 mg) in methanol ( 50 ml) and formaldehyde (50 ml; 37%) solution was stirred for 6 hours, the solvent was evaporated and the residue was dissolved in water, extracted 3 times with CHC13, the separated organic layer was dried (MgS04), filtered and The solvent was evaporated and the residue was stirred in ether, filtered and dried to give 9.7 g (86.6%) of the product. A portion of the sample (2.5 g) was recrystallized from ethyl acetate. The precipitate was filtered and dried to yield 0.49 g of 1- ( Diphenylmethyl) -3- (hydroxymethyl) -2-imidazolinone (Intermediate 4; melting point 133.5 ° C). A mixture of intermediate 4 (8.4 g) and tribenzylphosphonium bromide (10.3 g) in B (100 ml) was stirred and refluxed for 1 hour. After the solvent was evaporated, the residue was dissolved in toluene and boiled to precipitate. The product was filtered and dried to yield 17.5 g (96.2 ° /.) Of triphenyl bromide [3- (diphenylmethyl) -2,3-dihydro-2-one-l-1H-imidazole-1-methyl] Town (intermediate 5). V. Description of the invention (谙 Read the precautions on the back before writing ¥.)-Install the printed example of the employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A.3 Use bromobenzene (18.M grams), magnesium spinner (2.9 G), iodine (catalyst amount) and aluminum (catalyst amount) to form a Gngnard reagent in THF (105 ml), and a solution of bromine in THF (100 ml) was added dropwise to the magnesium bar under a stream of ^^ 2 Stir the solution with iodine in THF (5 ml), stir and heat the reaction mixture. After all the bromine is added, stir and reflux the reaction mixture for 1 hour. Cool the mixture in an ice bath, dropwise at 0 ° C. Add a solution of 3- (cyclopentyloxy) -4-methoxybenzaldehyde (22.03 g) in THF (80 ml), stir the reaction mixture at room temperature for 2 hours, and then cool to -33- Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm)-^ m:-IJ 4 24087 — A7 ______B7 V. Description of invention () Printed by the Employees ’Cooperative of the Intellectual Property Bureau of the Ministry of Economy 2- [3-cyclopentyloxy) -4-methoxyphenyl] ethynyl] -1,3-di _ 2H-imidazolidone (Compound 2) and 50 mg of Zl- [2- [3-cyclopentyloxy] -4-methyllactylbenzyl] ethoxy] dihydro-2H-weitu butterfly (Compound 3 ). Step 2 Stir the solution of Intermediate 3 (1g) and triethylsilane (1ml) in CH2C12 (00ml) at 0-3 ° C. Add trifluoroacetic acid (0_68ml) to CH2C12 (50ml) dropwise. Ml) solution for 2 hours, the resulting reaction mixture was allowed to warm to room temperature, and then stirred for 48 hours. The solution was neutralized with solid Na2C03, filtered and the filtrate was evaporated. The residue was purified via silica gel in a glass filter (Eluent: CH2C12 / CH30H 90/10). Collect the pure eluate and evaporate the solvent to recrystallize the residue from CH3CN. The precipitate was filtered, washed with CH3CN and DIPE, and then dried to yield 0.4 g (41.6 %) (£) -1- [2- (3-Cyclopentyloxy |) -4-methoxyphenyl] -2-phenylvinyl] · 1,3-dihydro-2H-amizole-2 -Ming (Compound 2). Example B.2 a) Stir a mixture of sodium argon (2.88 g; 50%) in THF (250 ml) at room temperature under a flow of 1 ^ 2, and add (diethyllinyl) ethyl picanoate dropwise. (13.45 g) 4 Keep the temperature below 15 ° C, stir the reaction mixture for 30 minutes, add the intermediate 2 (6.32 g) in portions, continue stirring for 1 hour, cool the reaction mixture in an ice bath and use NH4C1 solution Decompose and extract the aqueous layer 3 times with CH2C12. The separated organic layer is dried (M g S 0 4), filtered; the solvent is evaporated, and the residue is purified on the broken gel by column chromatography (eluent) ： CH2C12 / C2H50H 95/5), collect pure solution ~ 36 ~ This paper scale uses China National Standards (CNS) Α4 is present (210X297) 嫠 {Please read the precautions on the back before ^ Smart copy 1- Binder-binding ---- 'Table ---------------- 424087 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of Invention () Example B.3 10 (2.04 g) was stirred in a mixture of THF (120 ml) and argon acid (6 ml; equivalent concentration) and refluxed for 8 hours to cool the reaction mixture It was basified with K:! CO3 solution and the solvent was evaporated. The residue was dissolved in water and extracted with ch2ci2. The separated organic layer was dried (MgSod, filtered, and the solvent was evaporated. Column chromatography Purify the residue on silica gel (eluent: 0.5% ammonium acetate in water / (: 1 &quot; 13〇 "99.5 / 0.5), collect the required eluate and evaporate the solvent, and stir the residue in DIPE After filtering and drying, 0.38 g (11.7%) of 1- [2- (3,4 -methyllactylphenyl) -2-phenylethenyl] -2 -weiyezheng S is the same (compound 8: Melting point (55.3 ° C). Example B.4, A mixture of intermediate 10 (2 g) in acetic anhydride (20 ml) was stirred and ... refluxed for 6 hours, the solvent was evaporated and toluene was added twice and Evaporate again and purify the residue on silica gel by column chromatography (eluent: CH2C12 / CH30H 98/2). Collect the pure eluate and evaporate the solvent to produce 1.2 g of product. This part was analyzed by HPLC on silica gel. Purification (eluent: CH2C12 / CH30H 98/2), the pure eluate was collected and the solvent was evaporated to produce 1.02 g of product, which was crystallized from ethyl acetate, After the precipitate was filtered and dried, 0.53 g (24.8%) of 1-ethylfluorenyl-3- [2- (3,4-monomethoxymethylene) -2 -fenylethenyl] -2 · Biting S is the same as (Compound 9). This paper size applies to Chinese national standards (CNS M4 specification (210X297 mm) Please read the notes on the back before filling out this page) Binding 1 · 424087 A7 B7 V. Description of invention () .iL Supplement η Intellectual Property of the Ministry of Economic Affairs Example B.5 printed by the Bureau ’s Consumer Cooperatives Stir THF (200 ml) and add sodium hydride (0.84 g; 50%) at room temperature and> 12 flow, add intermediate 5 (6.05 g) in portions, and continue stirring Over 2.5 hours, intermediate 7 (2.96 g) was added and the reaction mixture was stirred for 16 hours. The mixture was cooled in an ice bath and decomposed with aqueous NH4CI solution, and then extracted 3 times with ether. The separated organic layer was dried (MgS. 4). Filtrate and evaporate the solvent. Purify the residue on silica gel by column chromatography (eluent · ί: Η2α2 / (: Η3ΟΗ 99/1). Collect the required eluate and evaporate the solvent. 6 g of product was produced, and this part was purified on silica gel by column chromatography (eluent: CH2C12 / CH30H 99.9 / 0.1). The pure eluate was collected and the solvent was evaporated to produce 1.2 g of eluate 1 and 1 _ 1 Grams of dissolve 2 and dissolve 1 in DIPE , Filtered and dried to yield 0.82 g (15%) of (E) -1- [2- [3- (cyclofluorenyloxy) -4-methoxyphenylb 2-phenylvinyl] -3 · (di Benzylmethyl) -1,3:, dihydro-2 ^ 1-imidazol-2-one (compound 10), and fraction 2 was stirred in DIPE, filtered, and dried to yield 0.57 g (10.5%) (2) -1- [2- [3- (cyclopentyloxy) -4-methoxyphenyl] · 2-phenylethenyl] -3- (diphenylmethyl) -1,3-dihydro -2H -Mijun-2 · * _ (Compound 11). Prepared in a similar manner: (Z) -1- [2- [3- (cyclopentyloxy) -4-methoxyphenyl]- 1-propenyldiphenylmethyl) -2H-imidazol-2-one (compound 12); (E) -1- [2- [3- (cyclofluorenyloxy) -4-methoxyphenyl ] -1-propenyl] -3_ (dibenzylmethyl) -2H-imidazole-2 · one (compound 13). -39- This paper uses China National Standard (CNS) A4 scale (210 X 297 mm) (Please read the precautions on the back before clicking this page) Patent application scope: A8B8C8D8 No. 85103446 Patent application ROC Patent Appln. No. 85103446 Amended application scope Chinese text-Attachment (1) Amended Claims in Chinese-(Enel. Ϊ) (March 89 &gt; 丨 Send) (Submitted on March), 2000) A compound of the formula 0) (Please read the precautions on the back of It before filling out this page) K ------ President of the Intellectual Property Bureau of the Ministry of Economy Formula or basic addition salts and their stereochemically isomeric forms, in which: R1 and R2 are independently of each other (V6 alkyl or 03-6 cycloalkyl; R3 is hydrogen; R4 is C, -6 alkyl, via Cyano, carboxyl or (V6 alkoxycarbonyl substituted CV6 halo, or benzyl; envy is hydrogen; Y is a direct bond; -AB- is a divalent group of the formula: -CH = CH- or -CH2- CH2-; L is hydrogen, (V6 alkylcarbonyl or CV6 alkyl substituted by phenyl. -46- J85IJ6-RE-CLAIM-CH Order --------- line ί This paper size is applicable to China Standard (CNS) A4 specification (210 * 297 mm)